A Phase 3 Open-Label, Randomized Study of LOXO-305 versus Investigator’s Choice of Idelalisib plus Rituximab or Bendamustine plus Rituximab in BTK Inhibitor Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN-CLL-321)
1. Age 18 or older per local regulations at time of enrollment.
2. Confirmed diagnosis by redacted local laboratory report of CLL/SLL as defined by iwCLL 2018 criteria.
3. A requirement for therapy consistent with iwCLL 2018 criteria for initiation of therapy.
4. Known 17p deletion status (wildtype or deleted).
5. Previously treated with a covalent BTK inhibitor, investigational or approved, and either alone or in combination with other agents.
6. Eastern Cooperative Oncology Group (ECOG) 0-2.
7. Must have adequate organ function.
8. Patients are required to have had the following washout periods prior to planned C1D1: a) Targeted agents or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter b) Therapeutic monoclonal antibodies: 4 weeks c) Palliative limited field radiation: 7 days d) Broad field radiation (>= 30% of bone marrow or whole brain radiotherapy): 28 days.
9. Prior treatment related AEs must have recovered to Grade <= 1, pretreatment baseline, or are controlled with medications without meeting other exclusion criteria (with the exception of alopecia). 10. Willingness of men and women of childbearing potential (WOCBP), and their partners, to observe barrier and/or highly effective birth control methods as outlined in Section 10.2 (Appendix 2 and below) for the duration of treatment and for 6 months following the last dose of study treatment or 12 months after the last dose of rituximab, whichever is later.
11. Willing and capable of giving signed informed consent.
12. Able to swallow oral study medication.
13. Able to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
1. Known or suspected Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocytic leukemia, or Hodgkin's lymphoma at any time preceding enrollment.
2. Known or suspected history of central nervous system(CNS) involvement by CLL/SLL.
3. Patients who experienced a major bleeding event on a prior BTK inhibitor.
4. Active second malignancy.
5. Major surgery, within 4 weeks of planned start of study treatment.
6. History of or ongoing drug-induced pneumonitis.
7. Ongoing drug-induced liver injury, primary biliary cirrhosis and/or extrahepatic obstruction caused by cholelithiasis and cirrhosis of the liver.
8. History of allogeneic or autologous SCT or CAR-T therapy within the past 60 days.
9. Active uncontrolled auto-immune cytopenia not on a stable regimen and dose for at least 4 weeks prior to study enrollment.
10. Significant cardiovascular disease.
11. Prolongation of the QT interval corrected (QTc) for heart rate using Fridericia's Formula (QTcF) > 470 msec on at least 2 of 3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs, during Screening.
12. Hepatitis B or hepatitis C testing indicating active/ongoing infection based on Screening laboratory tests.
13. Known active cytomegalovirus (CMV) infection.
14. Evidence of other clinically significant uncontrolled condition(s)
15. Known Human Immunodeficiency Virus (HIV) infection
16. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of the oral-administered study treatments.
17. Ongoing inflammatory bowel disease.
18. Prior exposure to non-covalent (reversible) BTK inhibitor.
19. Concurrent use of investigational agent or anticancer therapy except hormonal therapy.
20. Patients requiring therapeutic anticoagulation with warfarin or another Vitamin K antagonist.
21. Use of >= 20 mg prednisone QD or equivalent dose of steroid per day at the time of C1D1. Patients may not be on prednisone of any dose intended for antineoplastic use.
22. For patients planned to receive idelalisib.
23. Vaccination with a live vaccine within 28 days prior to randomization
24. Pregnancy, lactation, or plan to breastfeed during the study or within 30 days of the last dose of study treatment.
The purpose of this global study is to compare the efficacy and safety of pirtobrutinib administered as a continuous monotherapy versus Investigator's choice of two globally approved standards of care, idelalisib with rituximab (IdelaR) or bendamustine with rituximab (BR), in patients with previously treated CLL/SLL including for patients with 17p deletion (del 17p) who have received at least one prior regimen, including a BTK inhibitor.
